Throughout this application various publications are referenced and citations are provided in parentheses for them. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
Disorders of uric acid metabolism are extremely common. These disorders may afflict 1% or more of human individuals (Hall, A. P., et al., Am. J. Med. 42: 27, 1967; Heine, J., Virchow's Arch. f. Path. Anat., 260: 521, 1926; Decker, J. L. et al., Arth. Rheum. 5: 144, 1962). The best known example is gout which causes a painful, chronic arthritis which can be extremely debilitating and can lead to extensive deformities (Wyngarden, J. B. and Kelly, W. N., The Metabolic Basis of Inherited Disease, 916-1010, J. B. Stanbury, J. B. Wyngarden, D. S. Fredrickson, 4th ed. McGraw-Hill: New York, 1978; Bauer, W. and Krane, S. M., Disease of Metabolism, 805-849, G. G. Duncan, 5th ed., Saunders: Philadelphia, 1964).
Gout may be primary or secondary. Primary gout consists of hereditary diseases which are associated with increased serum uric acid levels (hyperuricemia). Secondary gout may occur in cancers, particularly leukemias, and in other blood disorders (e.g. polycythemia, myeloid metaplasia, etc.). There exists abundant evidence that prolonged elevations of serum uric acid are associated with the deposition of sodium urate crystals in many tissues, including kidney and joints.
A variety of disorders other than gouty arthritis are associated with abnormalities of uric acid metabolism, including kidney failure and urolithiasis (urinary stones composed of uric acid) which occur in 10-18% of patients with gout and which are common sources of morbidity and mortality from the disease (Talbott, J. H. and Terplan, K. L., Medicine 39: 405, 1960; Gutman, A. B. and Yu, T. F., Am. J. Med. 23: 600, 1957). Increased uric acid has also been associated with cardiovascular disease (Kramer, D. W., et al., Angiology 9: 162, 1958), plumbism (so-called "saturnine gout" caused by exposure to lead) (Ludwig, G. D., Arch. Int. Med. 100: 802, 1957), hyperparathyroidism (Mintz, D. H., et al., New Eng. J. Med. 265: 112, 1961), psoriasis, and sarcoidosis (Kaplan, H. and Klatzkin, G., Yale J. Biol. Med. 32: 335, 1960; Bunim, J. J., et al., Ann. Int. Med. 57: 1018, 1962).
Uric acid is derived from 3 major sources (1) an end-product of the synthesis of purines without prior incorporation into nucleic acids; (2) a breakdown product of tissue nucleic acids and pre-formed coenzymes; and (3) a product of the catabolism of dietary purine-containing compounds. At the pH of body fluids, uric acid generally exists in serum as the urate ion (monosodium urate). The mean normal serum concentration of uric acid is 5.1.+-.0.93 mg/100 ml. The normal range for females is approximately 1 mg/100 ml below the range for males. Uric acid is excreted by glomerular filtration and tubular secretion in the kidney. A substantial fraction of the material is also reabsorbed by the renal tubules.
Several methods have been used to treat disorders of uric acid metabolism and a variety of drugs have been employed to treat the acute manifestations of painful gouty arthritis. These drugs include colchicine, aspirin, and a variety of non-steroidal anti-inflammatory compounds. These drugs are extremely effective in reducing pain due to the acute attacks of gout; however, they do not prevent recurrent attacks and they do not affect the underlying disorders of abnormal uric acid metabolism. Methods used in clinical practice which more directly treat the metabolic disorder include increasing the excretion of uric acid by the kidneys and decreasing the formation of uric acid by inhibiting steps which precede its synthesis in the body.
Probenecid is an example of a compound which has been used to increase uric acid excretion (a so-called "uricosuric" drug). Probenecid causes an increase in uric acid secretion by the renal tubules and, when used chronically, can be useful in mobilizing body stores of urate (Gutman, A. B. and Yu, T. F., Trans. Acad. Am. Phys. 64: 279, 1951). However, a substantial porportion of patients treated with probenecid fail to respond. Twenty-five to fifty percent of patients fail to achieve reduction of serum uric acid to levels less than 6 mg/100 ml. Leading causes are drug intolerance, concomitant salicylate ingestion, and renal impairment (Gutman, A. B. and Yu, T. F., Lancet ii: 1258, 1957; Thompson, G. R., et al., Arth. Rheum. 5: 384, 1962). Approximately one-third of the patients eventually develop intolerance to the drug (Wyngarden, J. B. and Kelly, W. N., supra).
An example of a drug which inhibits uric acid formation is allopurinol. Allopurinol and other pyrazolo(3,4-d)pyrimidines were first synthesized for use as cancer chemotherapeutic agents. However, the drugs proved to have little anticancer activity when used singly (Shaw, R. K., et al., Cancer 13: 482, 1960). Allopurinol is structurally very similar to hypoxanthine, differing only in the transposition of the carbon and nitrogen atoms at positions 7 and 8. ##STR1##
The compound was subsequently shown to inhibit xanthine oxidase, an enzyme which is essential for the formation of uric acid (Feigelson, P., et al., J. Biol. Chem. 226: 993, 1957). Allopurinol is itself converted to oxy-purinol wherein an alcohol is attached to the carbon-2 position. Oxy-purinol is more potent in inhibiting xanthine oxidase, but oxy-purinol is less pharmaceutically acceptable due to low oral bioavailability. The observation that patients treated for cancer with allopurinol developed a decrease in serum uric acid suggested utility as a treatment for gout (Wyngarden, J. B., et al., Arth. Rheum. 6: 306, 1963). Allopurinol has since become a standard form of therapy for hyperuricemia and uric acid stones (Rundles, R. W., et al., Ann. Int. Med. 60: 717, 1964; Wyngarden, J. B., et al., Ann. Int. Med. 62: 842, 1965; Delbarre, F., et al., Arth. Rheum. 25: 627, 1966; Rundles, R. W., et al., Ann. Int. Med. 64: 229, 1966; Woodbury, D. M., The Pharmacological Basis of Therapeutics, L. S. Goodman and A. Gilman, 4th ed., MacMillan: New York, 1970). Although serious toxicity is uncommon, fatal reactions due to hypersensitivity, bone marrow suppression, hepatitis, and vasculitis have been reported (Wyngarden, J. B. and Kelly, S. M., supra). The incidence of side effects may total 20% of all patients treated with the drug (id.). Treatment for disorders of uric acid metabolism has not evolved significantly in the following two decades since the introduction of allopurinol.
The present invention relates to the use of barbituric acid derivatives which have undergone mono-substitution at the carbon-5 (C-5) position for treatment of disorders of uric acid metabolism. The method of the subject invention overcomes the disadvantages and side-effects associated with the methods of the prior art, particularly the disadvantages and side-effects associated with the use of allopurinol.
It has been discovered that administration of carbon-5 monosubstituted barbiturate compounds to humans and animals unexpectedly causes a dramatic decrease in the concentration of serum uric acid. Barbiturate compounds monosubstituted at the C-5 position with groups containing less than eight (8) alkyl carbons are especially suitable for clinical treatment of disorders of uric acid metabolism since they are orally bioavailable and do not readily penetrate the central nervous system. Thus, these compounds do not share the excessively sedating properties at doses which are effective for treatment of disorders of uric acic metabolism which characterize other barbiturate compounds which have undergone di-substitution at the C-5 position (Sharpless, S. K., in L. S. Goodman and A. Gilman, supra at 98-120).